Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury.

Locomotor training on treadmills can improve recovery of stepping in spinal cord injured animals and patients. Likewise, lesioned rats treated with antibodies against the myelin associated neurite growth inhibitory protein, Nogo-A, showed increased regeneration, neuronal reorganization and behavioural improvements. A detailed kinematic analysis showed that the hindlimb kinematic patterns that developed in anti-Nogo-A antibody treated versus treadmill trained spinal cord injured rats were significantly different. The synchronous combined treatment group did not show synergistic effects. This lack of synergistic effects could not be explained by an increase in pain perception, sprouting of calcitonin gene-related peptide (CGRP) positive fibres or by interference of locomotor training with anti-Nogo-A antibody induced regeneration and sprouting of descending fibre tracts. The differential mechanisms leading to behavioural recovery during task-specific training and in regeneration or plasticity enhancing therapies have to be taken into account in designing combinatorial therapies so that their potential positive interactive effects can be fully expressed.

[1]  P. London.  Injury , 1969, Definitions.

[2]  Adam R Ferguson,et al.  Two chronic motor training paradigms differentially influence acute instrumental learning in spinally transected rats , 2007, Behavioural Brain Research.

[3]  R. Jung,et al.  Recovery of locomotor function after treadmill training of incomplete spinal cord injured rats. , 2001, Biomedical sciences instrumentation.

[4]  T. Hökfelt,et al.  Calcitonin Gene‐Related Peptide in the Brain, Spinal Cord, and Some Peripheral Systems a , 1992, Annals of the New York Academy of Sciences.

[5]  K. Fouad,et al.  Nogo‐A antibody improves regeneration and locomotion of spinal cord–injured rats , 2005, Annals of neurology.

[6]  V. Edgerton,et al.  Use-Dependent Modulation of Inhibitory Capacity in the Feline Lumbar Spinal Cord , 2002, The Journal of Neuroscience.

[7]  A. Krassioukov,et al.  Calcitonin gene-related peptide immunoreactivity in chronic human spinal cord injury , 2007, Spinal Cord.

[8]  J C Pearson,et al.  Distribution of 5‐hydroxytryptamine‐immunoreactive boutons on α‐motoneurons in the lumbar spinal cord of adult cats , 1998, The Journal of comparative neurology.

[9]  V. Dietz,et al.  Treadmill training in incomplete spinal cord injured rats , 2000, Behavioural Brain Research.

[10]  M. Schwab,et al.  Lamina‐specific restoration of serotonergic projections after Nogo‐A antibody treatment of spinal cord injury in rats , 2008, The European journal of neuroscience.

[11]  S. Rossignol,et al.  Locomotor performance and adaptation after partial or complete spinal cord lesions in the cat. , 1999, Progress in brain research.

[12]  M. Schwab.  Nogo and axon regeneration , 2004, Current Opinion in Neurobiology.

[13]  T. Wannier,et al.  Intrathecally infused antibodies against Nogo-A penetrate the CNS and downregulate the endogenous neurite growth inhibitor Nogo-A , 2006, Molecular and Cellular Neuroscience.

[14]  K. Fouad,et al.  Functional switch between motor tracts in the presence of the mAb IN-1 in the adult rat , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Lemay,et al.  Neurotrophic factors promote and enhance locomotor recovery in untrained spinalized cats. , 2007, Journal of neurophysiology.

[16]  D. Basso,et al.  A sensitive and reliable locomotor rating scale for open field testing in rats. , 1995, Journal of neurotrauma.

[17]  K. Fouad,et al.  Anatomical Correlates of Locomotor Recovery Following Dorsal and Ventral Lesions of the Rat Spinal Cord , 2002, Experimental Neurology.

[18]  V. Edgerton,et al.  Hindlimb stepping movements in complete spinal rats induced by epidural spinal cord stimulation , 2005, Neuroscience Letters.

[19]  Bingbing Song,et al.  Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury , 2008, Nature Medicine.

[20]  S. Harkema,et al.  Retraining the injured spinal cord , 2001, The Journal of physiology.

[21]  Marco Schieppati,et al.  Tuning of a basic coordination pattern constructs straight-ahead and curved walking in humans. , 2004, Journal of neurophysiology.

[22]  C. Brösamle,et al.  `Semifree-floating' treatment: a simple and fast method to process consecutive sections for immunohistochemistry and neuronal tracing , 1997, Journal of Neuroscience Methods.

[23]  Noam Y. Harel,et al.  Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? , 2006, Nature Reviews Neuroscience.

[24]  Roland R Roy,et al.  Spinal Cord-Transected Mice Learn to Step in Response to Quipazine Treatment and Robotic Training , 2005, The Journal of Neuroscience.

[25]  M. Schwab,et al.  Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions , 1998, Nature Neuroscience.

[26]  C. Hulsebosch,et al.  Chronic central pain after spinal cord injury. , 1997, Journal of neurotrauma.

[27]  S. Harkema,et al.  Locomotor activity in spinal cord-injured persons. , 2004, Journal of applied physiology.

[28]  C. Hulsebosch,et al.  Spinal Cord Injury and Anti-NGF Treatment Results in Changes in CGRP Density and Distribution in the Dorsal Horn in the Rat , 1997, Experimental Neurology.

[29]  C. Hulsebosch,et al.  Direct evidence of primary afferent sprouting in distant segments following spinal cord injury in the rat: colocalization of GAP-43 and CGRP , 2003, Experimental Neurology.

[30]  J. Bloch,et al.  Nogo-A–specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates , 2006, Nature Medicine.

[31]  V. Edgerton,et al.  Plasticity of the spinal neural circuitry after injury. , 2004, Annual review of neuroscience.

[32]  A. B. Huber,et al.  Nogo-A Inhibits Neurite Outgrowth and Cell Spreading with Three Discrete Regions , 2003, The Journal of Neuroscience.

[33]  R. Dubner,et al.  A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia , 1987, Pain.

[34]  Dawn L. Merrett,et al.  Reaching training in rats with spinal cord injury promotes plasticity and task specific recovery. , 2007, Brain : a journal of neurology.

[35]  J. Schoenen,et al.  The effect of treadmill training on motor recovery after a partial spinal cord compression-injury in the adult rat. , 2003, Journal of neurotrauma.

[36]  Devin L Jindrich,et al.  OEG implantation and step training enhance hindlimb-stepping ability in adult spinal transected rats. , 2008, Brain : a journal of neurology.

[37]  V. Edgerton,et al.  Changes in Motoneuron Properties and Synaptic Inputs Related to Step Training after Spinal Cord Transection in Rats , 2007, The Journal of Neuroscience.

[38]  Roger Weber,et al.  Tools for understanding and optimizing robotic gait training. , 2006, Journal of rehabilitation research and development.

[39]  Hui Zhong,et al.  Kinematic and EMG determinants in quadrupedal locomotion of a non-human primate (Rhesus). , 2005, Journal of neurophysiology.

[40]  S. Strittmatter,et al.  The Nogo–Nogo Receptor Pathway Limits a Spectrum of Adult CNS Axonal Growth , 2006, The Journal of Neuroscience.

[41]  S. Rossignol,et al.  Recovery of locomotion after chronic spinalization in the adult cat , 1987, Brain Research.

[42]  Serge Rossignol,et al.  Prominent Role of the Spinal Central Pattern Generator in the Recovery of Locomotion after Partial Spinal Cord Injuries , 2008, The Journal of Neuroscience.

[43]  Serge Rossignol,et al.  Activation of Locomotion in Adult Chronic Spinal Rats Is Achieved by Transplantation of Embryonic Raphe Cells Reinnervating a Precise Lumbar Level , 2000, The Journal of Neuroscience.

[44]  David J. Reinkensmeyer,et al.  Hindlimb loading determines stepping quantity and quality following spinal cord transection , 2005, Brain Research.

[45]  V R Edgerton,et al.  Hindlimb locomotor and postural training modulates glycinergic inhibition in the spinal cord of the adult spinal cat. , 1999, Journal of neurophysiology.

[46]  Hui Zhong,et al.  Step Training Reinforces Specific Spinal Locomotor Circuitry in Adult Spinal Rats , 2008, The Journal of Neuroscience.

[47]  V R Edgerton,et al.  Full weight-bearing hindlimb standing following stand training in the adult spinal cat. , 1998, Journal of neurophysiology.

[48]  V. Dietz,et al.  Locomotor Recovery in Spinal Cord-Injured Rats Treated with an Antibody Neutralizing the Myelin-Associated Neurite Growth Inhibitor Nogo-A , 2001, The Journal of Neuroscience.

[49]  Roland R Roy,et al.  Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. , 2002, Journal of neurophysiology.

[50]  Adam R Ferguson,et al.  Nociceptive plasticity inhibits adaptive learning in the spinal cord , 2006, Neuroscience.